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A kind of preparation method of N-substituted tetrahydropyridine-3/4-boronic acid/ester

A technology of tetrahydropyridine and boric acid, which is applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as the lack of obvious advantages in the cost of the synthesis process, the small number of suppliers in the raw material market, and the troublesome hydrolysis of pinacol esters. High competitiveness and high reaction selectivity

Active Publication Date: 2022-05-17
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method needs to pass through coupling reaction, uses expensive palladium catalyst coupling, and raw material market supplier quantity is less
[0009] Although the above methods can realize the synthesis of such products to a certain extent, the methods lack versatility, and most of them need to be coupled with expensive metal palladium catalysts. The cost advantage of the synthesis process is not obvious, and they are all limited to boric acid For pinacol ester products, if you need to obtain the corresponding boric acid, it is relatively troublesome to hydrolyze the pinacol ester

Method used

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  • A kind of preparation method of N-substituted tetrahydropyridine-3/4-boronic acid/ester
  • A kind of preparation method of N-substituted tetrahydropyridine-3/4-boronic acid/ester
  • A kind of preparation method of N-substituted tetrahydropyridine-3/4-boronic acid/ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025]

[0026] In a 500mL three-necked flask, add pyridine-4-boronic acid pinacol ester (20.5g, 0.1mol), benzyl chloride (12.6g, 0.1mol) and chlorobenzene (110mL) successively, after stirring evenly, heat up to reflux reaction 5 Hours, detection of raw material reaction is complete. After the solvent was evaporated to dryness under reduced pressure, 33.2 grams of light yellow solid quaternary salt were obtained. Add this solid to 180 mL of tetrahydrofuran to form a suspension, cool to -10°C, and start adding sodium borohydride (4.2 g, 0.11 mol) in batches. During the addition process, there are obvious bubbles and violent exothermic heat. The temperature does not exceed 0°C. After the addition was complete, the mixture was naturally returned to room temperature and continued to stir for 2 hours, and TLC detected that the reaction was complete. Carefully quenched with saturated ammonium chloride solution, extracted with ethyl acetate, evaporated to dryness after merging t...

Embodiment 2

[0028]

[0029] In a 500mL three-neck flask, add pyridine-3-boronic acid pinacol ester (20.5g, 0.1mol), benzyl chloride (12.6g, 0.1mol) and chlorobenzene (110mL) successively, after stirring evenly, heat up to reflux reaction 5 Hours, detection of raw material reaction is complete. After the solvent was evaporated to dryness under reduced pressure, 33.5 g of light yellow solid quaternary salt was obtained. Add this solid to 180 mL of tetrahydrofuran to form a suspension, cool to -10°C, and start adding sodium borohydride (4.2 g, 0.11 mol) in batches. During the addition process, there are obvious bubbles and violent exothermic heat. The temperature does not exceed 0°C. After the addition was completed, the mixture was naturally returned to room temperature and stirred for 3 hours, and the reaction was detected by TLC. Carefully quenched with saturated ammonium chloride solution, extracted with ethyl acetate, evaporated to dryness after merging the organic layers, dissolve...

Embodiment 3

[0031]

[0032] In a 500mL three-neck flask, add pyridine-3-boronic acid pinacol ester (20.5g, 0.1mol) and dichloromethane 120mL in sequence, after stirring evenly, cool down to 0°C, and start adding MeI (14.9g, 0.105mol) dropwise After the dropwise addition is completed, continue the heat preservation reaction for 1 hour, then raise the temperature to reflux reaction for 5 hours, and detect that the reaction of the raw materials is complete. After the solvent was evaporated to dryness under reduced pressure, 34.9 grams of light pink solid quaternary salt were obtained. Add the solid to 240 mL of acetonitrile to form a suspension, cool to -10°C, and start adding sodium borohydride (4.2 g, 0.11 mol) in batches. During the addition, there are obvious bubbles and a violent exotherm. The temperature does not exceed 0°C. After the addition was complete, the mixture was naturally returned to room temperature and continued to stir for 5 hours, and TLC detected that the reaction w...

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Abstract

The invention discloses a preparation method of N-substituted tetrahydropyridine-3 / 4-boronic acid / ester, which belongs to the technical field of organic boric acid chemistry. Starting from pyridine-3 / 4-boronic acids / esters, reaction with halides to form quaternary salts, followed by reduction with sodium / potassium borohydride in aprotic solvents to N-substituted tetrahydropyridine-3 / 4-boronic acids / esters . In the present invention, easy-to-synthesize pyridine-3 / 4-boronic acid / ester is used as a raw material, and the product can be obtained through two continuous steps, and the reaction selectivity is high; it avoids the use of substituted piperidone as a raw material, which requires palladium-catalyzed coupling Or the defect of ultra-low temperature, this method has been verified on the 100-gram scale, providing a simple and efficient synthetic route for the preparation of this type of compound.

Description

technical field [0001] The invention relates to a preparation method of N-substituted tetrahydropyridine-3 / 4-boronic acid / ester, belonging to the field of synthesis of pharmaceutical intermediates. Background technique [0002] In the field of new drug research and development, the application of drugs with piperidine structural units is increasing, and there are many drugs in different clinical stages, for example: TRPV1 as the target code V-116517 is in the second phase of clinical treatment for chronic pain , Postherpetic neuralgia, acute pain. (refer to J.Med.Chem.2014,57,6781-6794 and US8575199B2.) [0003] Regarding the synthesis of aza six-membered cycloalkenyl boronic acid esters involved in this class of structural drugs, there are mainly the following methods: [0004] In the literature method, N-substituted-4-piperidone was used as raw material, and LiHMDS or LDA and PhNTf 2 The reaction generates alkenyl triflate, which is separated by column chromatography, f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/04C07F5/02
CPCC07F5/04C07F5/025Y02P20/55
Inventor 刘宗伦申海兵田利国王栋召王建凯
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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